ANTICOAGULAZIONE:attualità cliniche, di laboratorio e aspetti sociali
BOLOGNA, 21-22 GENNAIO 2016
Anticoagulanti e doppia antiaggregazione: la difficile convivenza tra FA, sindrome coronarica acuta e stenting coronarico.
Giuseppe Patti
Università Campus Bio-Medico di Roma
Convegno «Anticoagulazione: attualità cliniche, di laboratorio e aspetti sociali» Bologna, 21-22 Gennaio 2016
Ø Atrial Fibrillation 5% - 7% of the overall population referred for stenting have atrial fibrillation. Incidence of AF is increasing as the population ages Ø Prosthetic heart valves
Ø Previous systemic or venous thromboembolism Ø Left ventricular thrombus
Patients on anticoagulants and PCI
Bernard et al., Thromb Haemost 2013;110;560-568
ANTICOAGULAZIONE:attualità cliniche, di laboratorio e aspetti sociali
BOLOGNA, 21-22 GENNAIO 2016
Number of strategies in ACS pts with Atrial Fibrillation
ASA dose: None High (2) ASA duration (mo): 1 3 6 12 (4) ASA: 1+8=9 Thienopyridine: None Ticl Clop Prasu Tica (4) Thienopyridine duration (mo): 1 3 6 12 (4) Thieno 1+16=17 OAC: None Warf Dabi Riva Apix Edox (5) OAC INR/Dose: Low High (2) OAC: 1+10=11 Permutations of single, dual or triple Rx as early initial Rx (0,1,3,6 mo) after ACS: 9 x 17 x 11: 1,683 Permutations of single or dual Rx as early initial Rx (0,1,3,6 mo) during follow-up: 1,683
TOTAL PERMUTATIONS THROUGHOUT ONE YEAR: 2.8 million
RiskofBleedingwithSingle,DualorTripleTherapy
Non Fatal and Fatal Bleeding
Hansen ML et al. Arch Intern Med 2010
ANTICOAGULAZIONE:attualità cliniche, di laboratorio e aspetti sociali
BOLOGNA, 21-22 GENNAIO 2016
Ø 3-5 fold increase in major bleeding risk with triple Rx, with consequent increase
in MACE rates
Ø GI bleeding in 60% of cases
Ø Relationship between bleeding risk and duration of triple Rx (6 vs 1 mo.)
Ø Pts receiving VKAs have 2-fold lower ischemic stroke rates (vs dual antiPLT)
Ø High MI rates are paralleled by high stent thrombosis rates (DES)
Patti G. Cathet Cardiovasc Intv 2010
ANTICOAGULAZIONE:attualità cliniche, di laboratorio e aspetti sociali
BOLOGNA, 21-22 GENNAIO 2016
Bleeding events and clinical outcome
Ischemic risk
Bleeding risk
79ptswithBMSand86withDES-A6eronemonth:OAC+Clop.
One month of triple therapy after PCI: BMS vs. DES
MAC
E-free
Surviva
l
Pasceri V, Patti G et al. Cathet Cardiovasc Intv 2010
ANTICOAGULAZIONE:attualità cliniche, di laboratorio e aspetti sociali
BOLOGNA, 21-22 GENNAIO 2016
Different antithrombotic regimen in AF patients following MI and coronary intervention
Lamberts M et al., J Am Coll Cardiol 2013
12165 AF patients from Danish registry hospitalized for MI and/or PCI between 2001 and 2009
WOESTtrial(N=573pts)
Dewilde W et al. ESC Congress 2012, Munchen
Primaryendpoint:bleedingevents
Secondaryendpoint:ischemicevents
ANTICOAGULAZIONE:attualità cliniche, di laboratorio e aspetti sociali
BOLOGNA, 21-22 GENNAIO 2016
WOEST Limitations
SAFETY v Open label study v Safety results driven by non-major bleeding v Bleeeding excess in the triple Rx arm (vs previous literature data) v Femoral approach in 74% of pts v PPI in 20% of pts v Target INR was 2-3 (and not 2-2.5) v TTR in warfarin pts?
EFFICACY v Driven by non-cardiac death v Underpowered for ST v Low clopidogrel response unknown v 70% of pts had stable angina
Prasugrel in triple therapy
Sarafoff N et al., J Am Coll Cardiol 2013
377 pts who underwent DES implantation and were discharged with a triple therapy recommendation for 6 months or longer: 21 pts received prasugrel and
356 received clopidogrel
ANTICOAGULAZIONE:attualità cliniche, di laboratorio e aspetti sociali
BOLOGNA, 21-22 GENNAIO 2016
ü - Careful INR monitoring during VKAs; administer VKAs to achieve a slightly
lower target INR of 2 to 2.5 (even between 1.6 and 2 in selected cases)
ü - Liberal use of gastro-protective agents
ü - Keep ASA dose as low as possible and use standard clopidogrel maintenance dose
ü - Limit the duration of dual antiPLT Rx to the time necessary for stent endothelialization
ü - In case of bleeding:
- ASA may be discontinued
- reversal of VKAs or platelet transfusions (severe bleeding)
- maintain INR as close to 2 as possible (moderate bleeding)
ü - Second-generation DES. DES with bioabsorbable polymers?
ü - No extensive data with NOACs, newer antiplatelet agents, PAR-1 antagonists
Bleeding risk Ø Age > 75 yrs, low BMI Ø Major bleeding (<6 mo.) Ø Bleeding-prone GI or genito-urinary lesions Ø Previous haemorragic stroke Ø Uncontrolled HT Ø Malignancies Ø Haematol., renal, liver disorders
Ischemic risk Ø Large area of jeopardized myocardium (also including LM disease and MV disease) Ø LV dysfunction Ø Diabetes Ø ACS Ø ISR, small or long stents, multiple stents
Ø Atrial fibrillation with recent stroke/TIA Ø Atrial fibrillation with risk factors Ø Mechanical valve prosthesis Ø Recent thrombo-embolism Ø Hypercoagulable states
Thrombo-embolic risk
Individual-based approach
Patti G. Cathet Cardiovasc Intv 2010
ANTICOAGULAZIONE:attualità cliniche, di laboratorio e aspetti sociali
BOLOGNA, 21-22 GENNAIO 2016
DansALetal.CirculaPon2013
0
1
2
3
4
5
6
7
Dab.110 Dab.150 Warfarin
DualanK-PLT SingleanK-PLT NoanK-PLT
Concomitant Use of Antiplatelet Therapy with Dabigatran or Warfarin in the RE-LY trial
Major bleeding
%
5.4 5.5
6.3
Comparative bleeding outcomes from ROCKET-AF
Rivaroxaban Warfarin P
# Pts with bleeds 395 384 NS
# units/person (median) 2 2
# who received FFP 45 81 <0.0001
# who received PCCs 4 9
Stroke/embolism 4.7% 5.4%
All cause death 20.4% 26.1%
ANTICOAGULAZIONE:attualità cliniche, di laboratorio e aspetti sociali
BOLOGNA, 21-22 GENNAIO 2016
2015 ESC Guidelines on NSTE-ACS
Millionsofchoices,butaveryfewdata……
Ø 2.8 million strategies Ø 30 non-randomized, small-sized studies Ø 1 undersized CRT Ø 0 trials with NOACs and anti-PLT therapy Ø Ongoing use of warfarin/full doses NOACs plus ACS doses of DAPT despite known bleeding hazard Ø Need CRTs to evaluate combinations that optimize safety and efficacy
ANTICOAGULAZIONE:attualità cliniche, di laboratorio e aspetti sociali
BOLOGNA, 21-22 GENNAIO 2016
ANTICOAGULAZIONE:attualità cliniche, di laboratorio e aspetti sociali
BOLOGNA, 21-22 GENNAIO 2016
Anticoagulanti e doppia antiaggregazione: la difficile convivenza tra FA, sindrome coronarica acuta e stenting coronarico.
Giuseppe Patti
Università Campus Bio-Medico di Roma
Convegno «Anticoagulazione: attualità cliniche, di laboratorio e aspetti sociali» Bologna, 21-22 Gennaio 2016
Anticoagulanti e doppia antiaggregazione: la difficile convivenza tra FA, sindrome coronarica acuta e stenting coronarico.
Giuseppe Patti
Università Campus Bio-Medico di Roma
Convegno «Anticoagulazione: attualità cliniche, di laboratorio e aspetti sociali» Bologna, 21-22 Gennaio 2016
Outcome of patients with major bleeding while on Dabigatran vs Warfarin (5 CRTs; N=1,034)
Majeed A. Circulation 2013
Dabigatran: more transfusions, less plasma, more PCC/Rec. VII a, shorter ICU stay
9%
13%
OR: 0.66 (0.44-1.00); P=0.051
Ischaemic cardiac outcomes in patients with atrial fibrillation treated with vitamin K antagonism or factor Xa inhibition: results from the ROCKET AF trial
Mahaffey KW. Eur Heart J 2014
ANTICOAGULAZIONE:attualità cliniche, di laboratorio e aspetti sociali
BOLOGNA, 21-22 GENNAIO 2016
Retrospective comparison of Triple Rx vs Warf + Ticagrelor on 266 Swedish pts with ACS (52% STEMI)
Major bleeding MACE
Braun OO. Thromb Res 2015
ANTICOAGULAZIONE:attualità cliniche, di laboratorio e aspetti sociali
BOLOGNA, 21-22 GENNAIO 2016
Lamberts et al. J Am Coll Cardiol 2013
Registro Danese di 12165 pazienti con FA e IMA o PTCA Tipo di Terapia alla Dimissione e Score Clinici
ANTICOAGULAZIONE:attualità cliniche, di laboratorio e aspetti sociali
BOLOGNA, 21-22 GENNAIO 2016
Douketis JD et al. Throm Haemost 2015
0
1
2
3
4
5
6
7
8
Warf.MB Warf.TE DabiMB DabiTE
Bridging Nobridging
Data from the RELY trial in pts undergoing elective surgery
% 6.8
1.6
P<0.001
0.5 0.2
P=0.32
6.5
1.8
P<0.001
0.5 0.3
P=0.46
ANTICOAGULAZIONE:attualità cliniche, di laboratorio e aspetti sociali
BOLOGNA, 21-22 GENNAIO 2016
Type of surgery
Trough concentrations (skip one BID dose, 18-24 hrs for OD; restart 6-8 hrs after, even for spinal anest. Or spinal puncture)
Lamberts M et al., Circulation 2012:126;1185.1193
Bleeding events among different antithrombotic regimen
Crude incidence rates of fatal and nonfatal bleeding according to antithrombotic regimen
ANTICOAGULAZIONE:attualità cliniche, di laboratorio e aspetti sociali
BOLOGNA, 21-22 GENNAIO 2016
NOAC Last drug intake before elective surgery
Heidbuchel et al. Europace 2013
Caution with regard to time of interruption: - Liver impairment - Older age - Co-medications - History of bleeding ….. Laboratory tests/serum concentrations ….. Reversal agents
NOAC Restoration after surgery
Low bleeding risk and high thromboembolic risk - 24 hours
Low bleeding risk and low thromboembolic risk - 48 hours
High bleeding risk and high thromboembolic risk - 48 to 72 hours on an individual basis
High bleeding risk and low thromboembolic risk - 72 hours
ANTICOAGULAZIONE:attualità cliniche, di laboratorio e aspetti sociali
BOLOGNA, 21-22 GENNAIO 2016
Background slides
ANTICOAGULAZIONE:attualità cliniche, di laboratorio e aspetti sociali
BOLOGNA, 21-22 GENNAIO 2016
Ø Patients on anticoagulant therapy undergoing PCI represent a high-risk population
Ø Treatment options offer great benefit but also pose potential harm
Ø Patient-specific risk assessment is advised
Ø “Ad hoc” prospective large studies with NOAC are needed, but encouraging data are expected
Conclusions
SAFE SURGERY: Choosing the Best Approach
1- What is the risk of bleeding with AC based upon the type of procedure and patient’s history?
2- What is the risk of thrombosis if AC reduced or stopped?
3- Other issues: time of OAC interruption/restoration; rebound effect?
Must Answer three basic questions
ANTICOAGULAZIONE:attualità cliniche, di laboratorio e aspetti sociali
BOLOGNA, 21-22 GENNAIO 2016
Months After Randomization
PrimaryEfficacyEnd-point:CVDeath/MI/Stroke(Ischemic+Hemorr.)
Rivaroxaban (both doses)
HR 0.84 (0.74-0.96) ARR 1.8%
P = 0.002
NNT = 59
10.7%
8.9%
Estim
ated
Cum
ulat
ive
Rat
e (%
) Placebo 2 Yr KM Estimate
Mega JL et al. N Engl J Med 2012
ANTICOAGULAZIONE:attualità cliniche, di laboratorio e aspetti sociali
BOLOGNA, 21-22 GENNAIO 2016
The SAMe – TT2R2 score
Apostolakis S. Chest 2013
A score 0-1 predicted a TTR >65%
Dabigatran vs warfarin in a real-world registry (N=13,914)
Larsen TB. J Am Coll Cardiol 2013
ANTICOAGULAZIONE:attualità cliniche, di laboratorio e aspetti sociali
BOLOGNA, 21-22 GENNAIO 2016
Triple therapy in STEMI: results from HORIZON-AMI
NikolskyEetal.AmJCardiol2012
3.8% of patients with STEMI undergoing primary PCI had an indication for oral anticoagulation with VKA
Oldgren J. Eur Heart J 2013
Pts with ACS while on anticoagulant therapy: addition of antiplatelet therapy
ANTICOAGULAZIONE:attualità cliniche, di laboratorio e aspetti sociali
BOLOGNA, 21-22 GENNAIO 2016
Comparative bleeding outcomes from ROCKET-AF
Rivaroxaban Warfarin P
# Pts with bleeds 395 384 NS
# units/person (median) 2 2
# who received FFP 45 81 <0.0001
# who received PCCs 4 9
Stroke/embolism 4.7% 5.4%
All cause death 20.4% 26.1%
LowHAS-BLED
HighHAS-BLED
0
20
40
60
80
100
HighCHADS Interm.CHADS LowCHADS
LowHAS-BLED HighHAS-BLED
Mannuni M. AHA 2013
AVIATOR-1: Triple therapy prevalence at discharge among different risk strata
%
49
50
39
41
22
28
ANTICOAGULAZIONE:attualità cliniche, di laboratorio e aspetti sociali
BOLOGNA, 21-22 GENNAIO 2016
Perzborn.ESC2010
0
10
20
30
40
50
60
ReducKonofThrombinformaKon(%)
ASA Clop.
ASA+Clop. Riva
Riva+ASA Riva+Clop.
Riva+ASA+Clop.
0,00
0,50
1,00
1,50
2,00
2,50
3,00
ProlongaKonofBleedingKme
ASA Clop.
ASA+Clop. Riva
Riva+ASA Riva+Clop.
Riva+ASA+Clop.
Addition of Rivaroxaban to anti-PLT therapy in rats
2014 ESC Guidelines on Myocardial revascularization
ANTICOAGULAZIONE:attualità cliniche, di laboratorio e aspetti sociali
BOLOGNA, 21-22 GENNAIO 2016
Oldgren J. Eur Heart J 2013
Pts on antiplatelet therapy after ACS: addition of anticoagulant
New oral anticoagulants in addition to single or dual antiplatelet therapy after ACS
Oldgren M et al., Eur Heart J 2013
ANTICOAGULAZIONE:attualità cliniche, di laboratorio e aspetti sociali
BOLOGNA, 21-22 GENNAIO 2016
New oral anticoagulants in addition to single or dual antiplatelet therapy after ACS
Oldgren M et al., Eur Heart J 2013
Months After Randomization
PrimaryEfficacyEnd-point:CVDeath/MI/Stroke(Ischemic+Hemorr.)
Rivaroxaban (both doses)
HR 0.84 (0.74-0.96) ARR 1.8%
P = 0.002
NNT = 59
10.7%
8.9%
Estim
ated
Cum
ulat
ive
Rat
e (%
) Placebo 2 Yr KM Estimate
Mega JL et al. N Engl J Med 2012
ANTICOAGULAZIONE:attualità cliniche, di laboratorio e aspetti sociali
BOLOGNA, 21-22 GENNAIO 2016
Outcome of patients with major bleeding while on Dabigatran vs Warfarin (5 CRTs; N=1,034)
Majeed A. Circulation 2013
Dabigatran: more transfusions, less plasma, more PCC/Rec. VII a, shorter ICU stay
9%
13%
OR: 0.66 (0.44-1.00); P=0.051
Which therapy? Ø Stratification of patients according their risk profile
Ø Risk score (HAS-BLED, CHADS2-VASC2, GRACE, CRUSADE)
ANTICOAGULAZIONE:attualità cliniche, di laboratorio e aspetti sociali
BOLOGNA, 21-22 GENNAIO 2016
Antithrombotic algorithm in patients with indication for oral anticoagulant therapy undergoing PCI
Patti G. Cathet Cardiovasc Intv 2010
Consensus document EHRA-EAPCI
Lip G et al, Eur Heart J 2010;31:1311-1318
ANTICOAGULAZIONE:attualità cliniche, di laboratorio e aspetti sociali
BOLOGNA, 21-22 GENNAIO 2016
Multiple therapeutic options q Dual Antiplatelet therapy with ASA and clopidogrel
q Triple therapy (VKA, ASA, clopidogrel)
q VKA with ASA
q VKA with clopidogrel
q Single antiplatelet therapy
q New anticoagulants
q More potent P2Y12 inhibitors (prasugrel, ticagrelor)
Lack of data from large randomized clinical trials
EffectsofApixabanvsWarfarinAmongPaPentsUsingandNotUsingAspirininARISTOTLE
HR ASA HR No ASA
Stroke or embolism
0.55 0.80
Major bleeding 0.77 0.65
Hemorrhagic stroke
0.40 0.51
Granger CB et al. N Engl J Med 2011